Fexofenadine microcapsules and compositions containing them

ABSTRACT

The present invention provides a pharmaceutical composition comprising taste-masked immediate release microcapsules which comprise fexofenadine and a water-insoluble polymer coating. These microcapsules and the pharmaceutical compositions comprising them have suitable drug content and desirable pharmaceutical properties, including a quick dissolution rate of fexofenadine combined with a taste masking effect.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/956,786 filed on Dec. 2, 2015, now U.S. Pat. No. 10,166,220, which isa continuation of U.S. application Ser. No. 14/049,818 filed on Oct. 9,2013, now U.S. Pat. No. 9,233,105, which is a continuation of U.S.application Ser. No. 12/959,113 filed on Dec. 2, 2010, now U.S. Pat. No.8,580,313, which claims priority to U.S. Provisional Application No.61/265,823 filed Dec. 2, 2009, and U.S. Provisional Application No.61/354,575 filed Jun. 14, 2010, each of which is herein incorporated byreference in its entirety for all purposes.

BACKGROUND

The most widely used dosage forms for oral administration includetablets and capsules. However, such dosage forms have severaldisadvantages. For example, it is estimated that 50% of the populationhave problems swallowing tablets (see Seager, 50 J. Pharmacol. andPharm. 375-382 (1998)). In particular, it is difficult for some elderlypersons to swallow tablets or capsules or to medicate children who areunable or unwilling to swallow tablets or capsules. This leads to pooror non-compliance with the treatment, and thus has a negative impact onthe efficacy of the treatment.

The bitter taste of many actives also precludes medications from beingeasily sprinkled onto food, a commonly used method of administeringmedications to children. Bitter tasting drugs-incorporated into chewabletablets are typically thickly coated mostly with water-insolublepolymers, such as ethylcellulose, to taste mask the drugs throughresisting fracturing of the coated drugs during tablet compressionand/or during chewing and concomitant leakage of the bitter active.Consequently, substantially complete release of the drug from suchchewable tablets in the gastrointestinal tract may take 2 hours orlonger. More recently, orally disintegrating tablet (ODT) dosage formshave been introduced, which rapidly dissolve or disintegrate in thebuccal cavity, and hence can be taken without water. Other convenientoral dosage forms include sachets and microparticle dispersions. Suchmedicines are convenient, particularly for the elderly and children.

Fexofenadine hydrochloride is a histamine H1 receptor antagonist, and isapproved for the treatment of seasonal allergic rhinitis and chronicidiopathic urticaria. However, formulating fexofenadine is complicatedby its low solubility at low pH (i.e., gastric) conditions. One typicalway of addressing low solubility is to formulate the drug in ODT (orallydisintegrating tablet) form. However, that approach is complicated bythe bitter taste of fexofenadine hydrochloride.

U.S. Pat. No. 6,723,348 describes the preparation of an orodispersabletablet (ODT) containing fexofenadine in the form of fexofenadinegranulated with additional excipients, then fluid bed coated with apolymer coating. However, the manufacturing process is relativelycomplex and requires multiple granulation, coating, and mixing steps.

It is an object of the present invention to provide microencapsulatedfexofenadine, by a simple process, in a taste-masked immediate releaseform.

SUMMARY OF THE INVENTION

The present invention provides taste-masked immediate releasemicrocapsules which comprise fexofenadine and a water-insoluble polymercoating and pharmaceutical composition comprising them. Co-granulatedfexofenadine microcapsules are also disclosed in the present inventions.These microcapsules and the pharmaceutical compositions comprising themhave suitable drug content and desirable pharmaceutical properties,including a quick dissolution rate of fexofenadine combined with a tastemasking effect.

The present invention also provides a process for preparing themicrocapsule and the co-granulated microcapsules and the pharmaceuticalcompositions comprising taste-masked immediate release microcapsuleswhich comprise fexofenadine and a water-insoluble polymer coating. Theprocess for microcapsules preparation includes the steps of: (a)dissolving a water-insoluble polymer in an organic solvent; (b)suspending fexofenadine in the organic solvent; (c) applying a coatingof the water-insoluble polymer onto the fexofenadine by phaseseparation; and (d) separating the microcapsules from the organicsolvent.

The pharmaceutical compositions of the present invention are useful forthe treatment of inflammation-related conditions, such as seasonalallergic rhinitis and chronic idiopathic urticaria. Accordingly, thepresent invention also provides a method for treating aninflammation-related condition in an individual. The method comprisesadministering to an individual in need thereof a pharmaceuticalcomposition comprising taste-masked immediate release microcapsules,wherein the microcapsules comprise fexofenadine and a water-insolublepolymer coating.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited herein are incorporated by reference for allpurposes.

As used herein, the term “coating weight” refers to the dry weight ofthe microcapsule coating divided by the weight of the entiremicrocapsule, multiplied by 100. For example, a coating weight of 20%means that for the given microcapsule, the coating constitutes 20% ofthe weight of the microcapsule.

As used herein, the term “average coating weight” refers to the meanvalue of the coating weight for a population of microcapsules. Forexample, if half of the microcapsules in a given population have acoating weight of 10% and the other half has a coating weight of 20%,the average coating weight for the given population of microcapsules is15%.

As used herein, the term “microcapsules” refers to a drug (e.g.,fexofenadine or a pharmaceutically salt, ester, and/or solvate thereof,or polymorph thereof) coated with a water-insoluble polymer coating.

As used herein, the term “microencapsulation” refers to a process ofcoating a drug with the water-insoluble polymer.

As used herein and unless otherwise specified, references to“fexofenadine” or a pharmaceutically acceptable salt, ester, and/orsolvate thereof, or polymorph thereof

As used herein, the term “API” means “active pharmaceutical ingredient”,e.g., fexofenadine or a pharmaceutically salt, ester, and/or solvatethereof, or polymorphs thereof.

The present invention provides microcapsules of fexofenadine, apharmaceutical composition comprising taste-masked immediate releasemicrocapsules which comprise fexofenadine and a water-insoluble polymercoating. Microcapsules of fexofenadine may be in the form ofco-granulated microcapsules and may comprise further inactiveingredients and excipients. In one embodiment of the present invention,the fexofenadine is fexofenadine hydrochloride.

The fexofenadine of the present invention may be crystalline oramorphous or combinations thereof. Any fexofenadine crystalline formsare included and can be used in the preparation of microcapsules,microcapsule granulate and co-granulated microcapsules of the presentinvention.

The water-insoluble polymer of the present invention may be anysuitable, pharmaceutically acceptable water-insoluble polymer that formsa coating around the fexofenadine particles, and thereby yieldsfexofenadine microcapsules exhibiting taste-masked and immediate releaseproperties. Examples of water-insoluble polymers which may be used inthe present invention include ethylcellulose, polyvinyl acetate,cellulose acetate, cellulose acetate butyrate, polyvinyl acetate,ammonio-methacrylate copolymers and mixtures thereof. In one embodiment,the water-insoluble polymer of the invention is ethylcellulose.

The amount and typo of polymer in the coating contributes towardregulating the release of the fexofenadine, making it possible tomodulate the degree of taste masking and/or the fexofenadine release. Inthe present invention the coating polymer is insoluble in water. Theaverage coating weight of the microcapsules of the present invention isfrom about 2% to about 40%, including about 5%, about 10%, about 13% 3about 15%, about 17%, about 18%, about 20%, about 25%, about 30%, about35%, or about 40%. Typically, the average coating weight of themicrocapsules of the present invention is from about 10% to about 20%.More typically, the average coating weight is from about 13% to about18%. In one embodiment of the present invention, the microcapsules havean average coating weight of about 15%.

The wettability of the water insoluble coating of the microcapsules maybe improved by treatment with surfactants. A surfactant layer may beapplied to the microcapsules by suspending them in a solution containingthe surfactant, or by fluid bed spraying process. The surfactantsolution includes at least one surfactant and optionally otheringredients such as glidants or antisticking agents. The surfactantshould be soluble in a solvent in which the coating polymer ispractically insoluble under the relevant conditions, such as, forexample, at room temperature. Suitable surfactants include sodiumdocusate (DOSS), sodium lauryl sulfate, sucrose fatty acid ester, Tween,Lutrol F68, sorbitan oleate, sorbitan laurate, etc. Other wetting agentsmay be chosen among: hydroxypropyl cellulose, polyethylene glycol 600,1000, 3350, and 6000. In one embodiment, the surfactant is in one sensew/w % to about 10 w/w %. Typically, the concentration of surfactant inthe solution is between about 0.25 w/w % and about 2 w/w %, or betweenabout 0.5 w/w % and about 1.5 w/w % or between 0.45 and 0.75 w/w %. Inone embodiment, the concentration of surfactant in the solution is about0.45, in another about 0.6 w/w %, in another about 0.75%, in anotherabout 1 w/w %, in still another about 1.5 w/w %. Methods for wetting arealso described in U.S. Pat. No. 6,509,034. A particular antistickingagent is silicon dioxide.

If necessary, one or more further protective coating layers (e.g.,Opadry Clear, etc.) may be applied onto the microcapsules of theinvention.

A further embodiment of the present invention is a granulate oftaste-masked fexofenadine microcapsules coated with a water-insolublepolymer.

In the present invention not less than 80% of the fexofenadinetaste-masked immediate release microcapsules have a particle sizedistribution (PSD) below 500 microns; preferably not less than 80% ofthe microcapsules have a PSD below 355 microns; even preferably, notless than 80% of the microcapsules have a PSD below 250 microns. In afurther embodiment not less than 80% of the microcapsules have particlesize distribution below 200 microns. The taste masked immediate releasemicrocapsules are also used for the preparation of the taste maskedimmediate release co-granulated microcapsules.

A further embodiment is a co-granulate of water insoluble coatedmicrocapsules and at least one inactive ingredient. The co-granulatesare obtained when the microcapsules are granulated with a portion of atleast one inactive ingredient.

Inactive ingredients may be chosen for example from the group consistingof sugar alcohol and saccharides, such as sucrose, xanthan gum,beta-cyclodextrin, xylitol, sorbitol, mannitol, lactose, arabitol,isomalt, glycerol, alginate, microcrystalline cellulose,carboxymethylcellulose or a mixture thereof. Disintegrants incombination with sugar alcohols or saccharides may also be suitableinactive ingredients to be added to the fexofenadine microcapsules orco-granulates.

The microcapsule co-granulate disclosed herein is composed ofmicrocapsules of fexofenadine having a water insoluble coating and atleast one inactive ingredient. Particular embodiments of ratios ofmicrocapsule: inactive ingredient(s) are between 1:3 and 1:10, between1:5 and 1:8, and between 1:6 or 1:7.

The fexofenadine microcapsule co-granulate of the invention has adissolution release comparable to that of the wetted microcapsules. Inone embodiment the particle size of the co-granulate is preferably below600 μm with a low amount of granules under 125 μm. The reduced amount offine fraction is relevant as this fraction is almost totally composed ofun-granulated microcapsules and the presence of high levels of thisfraction could be correlated to a low homogeneity of the co-granulate.

In one embodiment the co-granulate has the following characteristics:ratio 1:7; homogeneity variation <5.0%; fine fraction below 125 μm<5.0%; fraction over 600 μm <10.0%; process yield about 97.0%. Anotherparticular embodiment of the invention is where those co-granulateshaving the following characteristics: ratio 1:7; homogeneity variation<5.0%; fine fraction below 125 μm <5.0%; fraction over 600 μm <5.0%;process yield about 97.0%.

A further embodiment of the present invention is a blend of fexofenadinemicrocapsule co-granulate and at least an inactive ingredient granulate.The inactive ingredient granulate comprises one or more inactiveingredients, and may be chosen for example from the group consisting ofsugar alcohol and saccharide, such as sucrose, xanthan gum,beta-cyclodextrin, xylitol, sorbitol, mannitol, lactose, arabitol,isomalt, glycerol, alginate, microcrystalline cellulose,carboxymethylcellulose or a mixture thereof. Disintegrants incombination with sugar alcohols or saccharides may also be suitableinactive ingredients to be added to the co-granulates. Preferably theblend (also called bulk mix) has the microcapsule co-granulate and thegranulated inactive ingredient(s) in 1:1 ratio. The preferredco-granulate comprises fexofenadine microcapsule, sucrose and xanthangum, and the granulated inactive ingredient comprises sucrose.

A further embodiment of the present invention is a pharmaceuticalcomposition comprising the fexofenadine taste-masked microcapsulescoated with a water insoluble polymer. Said composition comprisesfexofenadine microcapsules and further at least one inactive ingredientthat may be granulated or ungranulated and/or at least one excipient.

In one embodiment of the invention the pharmaceutical composition of theinvention comprises fexofenadine microcapsule co-granulate blended withat least one inactive ingredient that may be granulated or ungranulated.A particular embodiment of the invention is where the pharmaceuticalcomposition has co-granulates of microcapsules and at least onegranulated inactive ingredient in 1:1 ratio.

The pharmaceutical compositions of the present invention provideimmediate release of the active ingredient, for example, fexofenadinehydrochloride. In one embodiment, the compositions of the presentinvention release at least about 60% of the fexofenadine hydrochloridewithin 15 minutes in pH 6.8 JP 2°nd fluid (Japanese Pharmacopeia). Inanother embodiment, the compositions of the present invention release atleast about 65% of the fexofenadine hydrochloride within 15 minutes inpH 6.8 JP 2°nd fluid. In still another embodiment, the compositions ofthe present invention release at least about 70% of the fexofenadinehydrochloride within 15 minutes in pH 6.8 JP 2°nd fluid. In yet anotherembodiment, the compositions of the present invention release at leastabout 75% of the fexofenadine hydrochloride within 15 minutes in pH 6.8JP 2°nd fluid. In yet another embodiment, the compositions of thepresent invention release at least about 80% of the fexofenadinehydrochloride within 15 minutes in pH 6.8 JP 2°nd fluid. In yet anotherembodiment, the compositions of the present invention release at leastabout 85% of the fexofenadine hydrochloride within 15 minutes in pH 6.8JP 2°nd fluid. In still embodiment, the compositions of the presentinvention release at least about 90% of the fexofenadine hydrochloridewithin 15 minutes in pH 6.8 JP 2°nd fluid. In another embodiment, thecompositions of the present invention release at least about 95% of thefexofenadine hydrochloride within 15 minutes in pH 6.8 JP 2°nd fluid.

In another embodiment, the compositions described above may be combinedwith at least one additional pharmaceutical excipient. Excipients foruse in the compositions or dosage forms of the present invention includefillers, diluents, glidants, disintegrants, binders, lubricants etc.Other pharmaceutically acceptable excipients include acidifying agents,alkalizing agents, preservatives, antioxidants, buffering agents,chelating agents, coloring agents, complexing agents, emulsifying and/orsolubilizing agents, flavors and perfumes, humectants, sweeteningagents, wetting agents etc.

Examples of suitable fillers, diluents and/or binders include, but arenot limited to, lactose (e.g., spray-dried lactose, α-lactose,β-lactose, Tabletose®, various grades, of Pharmatose, Microtose® orFast-Flo®), microcrystalline cellulose (e.g. Avicel PH101, Avicel PH102,Ceolus KG-802, Ceolus KG-1000, Prosolv SMCC 50 or SMCC90, various gradesof Elcema®, Vivacel®, Ming Tai® or Solka-Floc®, hydroxypropylcellulose,L-hydroxypropylcellulose (low substituted), hydroxypropylmethylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH ofShin-Etsu, Ltd, such as, e.g., the 4,000 cps grades of Methocel E andMetolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH,the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000,15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulosepolymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C,Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose,carboxymethylhydroxyethylcellulose and other cellulose derivatives,sucrose, xanthan gum, cyclodextrin (e.g., beta-cyclodextrin), agarose,sorbitol, mannitol, dextrins, maltodextrins, starches or modifiedstarches (including potato starch, maize starch and rice starch),calcium phosphate (e.g., basic calcium phosphate, calcium hydrogenphosphate, dicalcium phosphate hydrate), calcium sulfate, calciumcarbonate, sodium alginate, collagen etc. or combinations thereof.

Specific examples of diluents include. e.g., calcium carbonate, dibasiccalcium phosphate, tribasic calcium phosphate, calcium sulfate,microcrystalline cellulose, powdered cellulose, dextrans, dextrin,dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch,pregelatinized starch, sucrose, xanthan gum, beta-cyclodextrin, etc. andcombinations thereof.

Specific examples of glidants and lubricants include, e.g., silicondioxide, stearic acid, magnesium stearate, calcium stearate or othermetallic, stearates, talc, waxes and glycerides, light mineral oil, PEG,glyceryl behenate, colloidal silica, hydrogenated vegetable oils, cornstarch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates,sodium benzoate, sodium acetate etc.

Other excipients include, e.g., flavoring agents, coloring agents,taste-masking agents, pH-adjusting agents, buffering agents,preservatives, stabilizing agents, anti-oxidants, wetting agents,humidity-adjusting agents, surface-active agents, suspending agents,absorption enhancing agents, agents for modified release etc.

Non-limiting examples of flavoring agents include, e.g., cherry, orange,banana, strawberry or other acceptable fruit flavors, or mixtures ofcherry, orange, and other acceptable fruit flavors, at up to, forinstance, about 3% based on the tablet weight. In addition, thecompositions of the present invention is can also include one or moresweeteners such as aspartame, sucralose, or other pharmaceuticallyacceptable sweeteners, or mixtures of such sweeteners, at up to about 2%by weight, based on the tablet weight. Furthermore, the compositions ofthe present invention can include one or more FD&C colorants at up to,for instance, 0.5% by weight, based on the tablet weight.

Antioxidants include, e.g., ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,monothioglycerol, potassium metabisulfite, propyl gallate, sodiumformaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate,sulfur dioxide, tocopherol, tocopherol acetate, tocopherolhemisuccinate, TPGS or other tocopherol derivatives, etc.

The fexofenadine microcapsules or the co-granulated microcapsules of theinvention may be formulated into a variety of final dosage formsincluding tablets (e.g., orally disintegrating chewable, dispersible,fast dissolving, effervescent), hard gelatin capsules and sprinkle,suspensions, sachets for permanent or extemporaneous suspensions, andsachets for direct administration in the mouth.

The microcapsules or the co-granulated microcapsules of the invention ormixture thereof may also be formulated into a dry syrup in presence ofsuitable inactive ingredients and possible further excipients. A drysyrup formulation is a fast dissolving powder that is formulated forease of swallowing. It may be administered directly in powder form, orfirst hydrated with a liquid, for example with 3-5 mL of water in atablespoon or 15-50 mL of water in a glass. Methods of carrying out drysyrup formulations are described in U.S. Publication No. 2008/0064713,herein incorporated by reference for all purposes.

The preferred dry syrup consists of fexofenadine taste maskedmicrocapsule co-granulate in 1:1 ratio to the granulated inactiveingredients; the co-granulate has the following characteristics:microcapsules are in ratio 1:7 to the inactive ingredient; theco-granulates contains sucrose and xanthan gum, the granulated inactiveingredient comprises sucrose. The fexofenadine dry syrup according tothe present invention has physico-chemical properties such as particlesize, dissolution rate the taste masking that are very little affectedby the filling step. This dry syrup has high homogeneity. In oneembodiment of the invention the co-granulate has homogeneity variation<5.0%; fine fraction below 125 μm<5.0%; fraction over 600 μm<5.0%;process yield about 97.0%;

The dry syrup is filled into sachet or stick-pack. A sachet is chosenaccording to the ability to properly dose the product, to the minimumfilling weight achievable, to the impact of the mechanical stress on thegranulate; to the use of different packaging configuration For flatsachet and the different filling weights any known packaging may beused. Particular filling weights are 300 and 600 mg, they are hereinapplied in the preparation of very low dosage strengths of themedicament (15 and 30 mg). The final packaging may have differentconfigurations, such as stick pack or flat pack; one example ofpackaging may consist in five boxes in line linked together with a PEfilm.

The fexofenadine taste-masked microcapsules of the present invention maybe prepared by coacervation, which is an effective technology forproducing taste-masked microcapsules. The coacervation process involvessalting out macromolecules into liquid-like colloidal, droplets ratherthan solid or gel aggregates. Coacervation may be carried out asdescribed in U.S. Pat. Nos. 5,252,337, 5,639,475, 6,139,865 and6,495,160, the entire contents of which are expressly incorporated byreference herein for all purposes.

The microcapsules of the present invention may be prepared by providinga homogeneous solution of a water-insoluble polymer in a suitablesolvent in which the active ingredient and, optionally, coatingadditives are dispersed in suspension. Phase separation may then beemployed to cause insolubilization of the water-insoluble polymer, whichgels (coacervates) around the active ingredient particles to form themicrocapsules. Phase separation may be performed, for example, throughvariation in temperature or in pH or by adding to the organic solvent aphase-separation inducing agent (i.e., a phase inducer agent) that causeinsolubilization of the water-insoluble polymer. Finally, themicrocapsules obtained are subjected to hardening, if required, andrecovered.

More specifically, the process for preparing taste-masked immediaterelease particles according to the present invention includes thefollowing steps: (a) dissolving a water-insoluble polymer in an organicsolvent; (b) suspending fexofenadine in the organic solvent; (c)applying a coating of the water-insoluble polymer onto the fexofenadineby phase separation; and (d) separating the microcapsules from saidorganic solvent, for example by filtering, centrifuging; and (e)removing residual organic solvent by drying the microcapsules.

As discussed above, the phase separation step may be carried out byvariation in temperature or in pH, or by adding to the organic solvent aphase inducer agent that cause insolubilization of the water-insolublepolymer. In one embodiment, the phase separation step is performed byadding to the organic solvent a phase inducer agent. Suitable phaseinducer agents which may be used in the present invention includepolyethylene; polyisobutylene, butyl rubber, polybutadiene, isoprenemethacrylic polymers, organosilicon polymers such as polydimethylsiloxane, paraffin, etc. In one embodiment, the phase inducer agent ispolyethylene.

The organic solvent may be a single organic solvent or it may include amixture of organic solvents. In accordance with the coacervationprocess, the organic solvent is chosen so as to dissolve the coatingpolymer, but not the active ingredient. Suitable organic solventsinclude cyclohexane or other hydrocarbon solvents. In one embodiment,the organic solvent is cyclohexane.

Non-limiting examples of suitable water-insoluble polymers includeethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinylacetate, neutral methacrylic acid-methylmethacrylate copolymers, andmixtures thereof. In one embodiment of the process for preparingtaste-masked immediate release particles according to, the presentinvention, the water-insoluble polymer is ethylcellulose, the phaseinducer agent is polyethylene, the solvent is cyclohexane and thefexofenadine is fexofenadine hydrochloride.

The taste masked fexofenadine microcapsules co-granulates are preparedby co-granulating the microcapsules (prepared as described above) withan inactive ingredient (eg sugar alcohol and/or saccharide) in form offine powder in a fluid bed by spraying a binder solution. The processcomprises the following steps: 1) microencapsulating of fexofenadine; 2)optional wetting of the microcapsules; 3) adding wetted or unwettedfexofenadine microcapsules to inactive ingredient(s); 4) spraying of thebinding solution; 5) drying of the granules; and 6) sieving of thegranules.

Granulation may be carried out in a conventional granulator according toconventional techniques. The binder solution is composed of one or moreinactive ingredients, preferably is composed of two inactiveingredients; this is particularly suitable to obtain an efficientgranulation of the microcapsule with the sucrose. The binder solution ispreferably composed of sucrose and xanthan gum. Other inactiveingredients may be chosen from the group consisting of sugars, sugarsalcohols, saccharides, sugar/sugar alcohol in combination withdisintegrants.

The following parameters are kept under control during this process: theamount of binder solution; the ratio between wet microcapsules and theinactive ingredient(s); the spray rate of the binding solution; theatomization pressure; the air flow. The drying of the granules are isperformed under the same controlled conditions of inlet air temperature,inlet air flow, etc. The granules are sieved trough a stainless steelnet of 840 μm.

The co-granulate is then blended with the inactive ingredient(s)granulate. The final blend comprises the above co-granulate and theinactive ingredient(s) granulate. In a particular embodiment thispharmaceutical composition has the co-granulate and the granulatedinactive ingredient(s) in a 1:1 ratio.

Particular inactive ingredient(s) granulate is composed of sucrose. Thegranulate is obtained by a process comprising the following steps: 1)adding the inactive ingredient(s); 2) spraying of the binding solution;3) drying of the granules; and 4) sieving and calibrating. During thisprocess the following experimental conditions are controlled: the amountof powder granulated; the spray rate of the solution; the atomizationpressure; and the humidity of the in-let air. The air flow is keptconstant. All the drying steps are performed in the same conditions(inlet air temperature, inlet air flow, etc.). The granules are sievedtrough a stainless steel net of 600 μm or 840 μm. The granules biggerthan 840 μm are forced trough a 20,600 μm screen granulator.

The mixing of the co-granulate, the inactive ingredient(s) granules,together with further ingredients (such as flavour, glidants) isperformed under controlled rotation speed for suitable mixing time.

The process of preparation of fexofenadine dry syrup comprises thefollowing different steps: 1) micrococapsulating fexofenadine 2)optional wetting of microcapsules; 3) co-granulating of wetted orunwetted microcapsules with at least one inactive ingredient (such assucrose); 4) separately granulating of inactive ingredient(s) (such assucrose); 5) mixing of co-granulate of fexofenadine obtained in step 3)together with the granulated inactive ingredient(s) (such as sucrose)obtained in step 4) and with optional further ingredients (such asflavors and silicon dioxide); and 6) filling of fexofenadine dry syrupbulk mixture of step 5) in sachets.

The present invention further provides a method for treating aninflammation-related condition in an individual. The method comprisesadministering to an individual in need thereof a pharmaceuticalcomposition comprising taste-masked immediate release microcapsules,wherein the microcapsules comprise fexofenadine and a water-insolublepolymer coating. Inflammation-related conditions which may be treatedaccording to the present invention include seasonal allergic rhinitisand chronic idiopathic urticaria.

The dose of fexofenadine hydrochloride to be administered to anindividual may vary depending on the age of the individual being treatedas well as the indication. Common doses of fexofenadine hydrochlorideare 15 mg twice daily, 30 mg twice daily, 60 mg twice daily and 180 mgonce daily. Consequently, final dosage forms prepared with thecompositions of the present invention may include, for example, 15 mg offexofenadine hydrochloride, 30 mg of fexofenadine hydrochloride, 60 mgof fexofenadine hydrochloride or 180 mg of fexofenadine hydrochloride.

The following examples are provided for purposes of illustration, andshould in no way be construed to limit the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Photomicrographs of fexofenadine microcapsules in cyclohexaneSample 1 (average Ethylcellulose weight 10%).

FIG. 2: Photomicrographs of fexofenadine microcapsules in cyclohexaneSample 2 (average Ethylcellulose weight 13%).

FIG. 3: Photomicrographs of fexofenadine microcapsules in cyclohexaneSample 3 (average Ethylcellulose weight 15%).

FIG. 4: Photomicrographs of fexofenadine microcapsules in cyclohexaneSample 5 (average Ethylcellulose weight 17%).

FIG. 5: Photomicrographs of fexofenadine microcapsules in cyclohexaneSample 6 (average Ethylcellulose weight 20%).

FIG. 6: Photomicrograph of microcapsule Sample 4-15% Ethylcellulose(magnification 2.5×).

FIG. 7: Photomicrograph of microcapsule Sample 7-20% Ethylcellulose(magnification 2.5×).

FIG. 8: The particle size distribution (PSD) of microcapsules with a 15%Ethylcellulose.

FIG. 9: The dissolution profiles of fexofenadine microcapsules,Ethylcellulose 15%, in buffer pH 6.8 2^(nd) fluid JP (n=6)

FIG. 10: Dissolution profiles of fexofenadine microcapsules, with orwithout 0.5 mL of DOSS 0.01M in the dissolution media.

FIG. 11: Dissolution profiles of fexofenadine from industrial wettedmicrocapsules buffer pH 6.8 2^(nd) fluid JP (n=6).

FIG. 12: Dissolution rate of fexofenadine from microcapsules with threedifferent average Ethylcellulose weight levels.

FIG. 13: Dissolution profiles at pH 6.8 2°nd fluid JP of wettablemicrocapsules at different Ethylcellulose levels.

FIG. 14: Dissolution profiles of fexofenadine microcapsules in differentdissolution media.

FIG. 15: Particle size analysis of SG granulate (SAMPLE 68), fractionselected 250-600 μm.

FIG. 16: Particle size analysis of SGX granulate (SAMPLE 69), fractionselected 250-600 μm.

FIG. 17: Particle size analysis of SβCD granulate (SAMPLE 70), fractionselected 250-600 μm.

FIG. 18: Dissolution rate of fexofenadine from microcapsules with 13%average ethylcellulose weight.

FIG. 19: Dissolution rate of fexofenadine from formulations containingmicrocapsules with 17% average ethylcellulose weight.

FIG. 20: Dissolution rate of fexofenadine from formulated and plainmicrocapsules with 20% average Ethylcellulose weight.

FIG. 21: Dissolution profiles at pH 6.8 (2° fluid JP) of microcapsules13% ethylcellulose (SAMPLE 8) and the corresponding prototypes SAMPLE36-SAMPLE 32.

FIG. 22: Dissolution profiles at pH 6.8 (2° fluid JP) of microcapsules17% Ethylcellulose (SAMPLE 9-D) and the corresponding prototypes SAMPLE37-SAMPLE 39-SAMPLE 33.

FIG. 23: Dissolution profiles at pH 6.8 (2° fluid JP) of microcapsules20% Ethylcellulose (SAMPLE 6-D2) and the corresponding prototype SAMPLE38.

FIG. 24: Dissolution rate of 13% average coating weight microcapsules(SAMPLE 8) in various dissolution media.

FIG. 25: Dissolution rates of formulated product containing 13% averageethylcellulose weight microcapsules (SAMPLE 32) in various dissolutionmedia.

FIG. 26: Dissolution rates of 17% average coating weight microcapsules(SAMPLE 9-D) in various dissolution media.

FIG. 27: Dissolution rates of formulated product containing 17% averageethylcellulose weight microcapsules (SAMPLE 33) in various dissolutionmedia.

FIG. 28: The radar graph describes the influence of the processparameters onto the formation of small particles.

EXPERIMENTAL PART

1. Fexofenadine Microcapsules

1.1 Methods and Equipment for Fexofenadine Microcapsules Preparation

Cyclohexane is poured into the microencapsulation reactor. Then, undercontinuous stirring, fexofenadine HCl, ethylcellulose (EC) andpolyethylene are added. The mixture is heated and then cooled down.Microcapsules are recovered, and then washed (one or more times),filtered, and dried over night (about 16 h) in a fume hood or in a hoodat 40° C. The powder is sieved through a 300 μm opening sieve.

TABLE 1 The Process Flow Sheet COMPONENT Fexofenadine, Ethylcellulose,Epolene¹, Cyclohexane² STEP COACERVATING with PHASE SEPARATION WASHINGFILTERING DRYING SIEVING EQUIPMENT Reactor Temperature emo controllingsystem Stirrer, Filtering system Filtering system Hood, Oven Sieve¹removed during washing step ²removed during drying step

Several batches of microcapsules are prepared; the amount of theethylcellulose coating (% w/w, calculated as microcapsule weight gain)in the final microcapsules is summarized in Table 2.

TABLE 2 Average Coating Weight of Microcapsules Lot Coating Weight (%)SAMPLE 1 10 SAMPLE 2 13 SAMPLE 3 15 SAMPLE 4 15 SAMPLE 5 17 SAMPLE 6 20SAMPLE 7 20

The microcapsules are characterized by appearance, particle sizedistribution, residual solvent content and dissolution rate. Microscopicevaluation at the end of the microencapsulation process of the fivebatches shows appropriate polymer coating deposition around thefexofenadine particles consistent with the amount of the polymer that isused to prepare the different batches (see FIGS. 1-5).

As shown in FIGS. 6 and 7, an increase in particle size and level ofagglomeration of the microcapsules is found to be proportional to theamount of polymeric coating that is applied. The very small particles offexofenadine undergo a process akin to granulation, and form discreteparticulate clusters in the 50 to 200 micron size range; cluster size isseen to increase with polymer level.

The particle size distribution (PSD) of microcapsules with a 15% coatingis measured (generated from SAMPLE 3). An amount of microcapsules in therange of 25 g-50 g is poured into a 100 mL HDPE bottle, 0.2% (w/w) ofSyloid 244 (colloidal silicon dioxide, WR Grace, Columbia, Md.) issieved through 150 μm screens, added to the microcapsules and manuallyblended, for 2 minutes. The mixture of microcapsules and Syloid 244 issieved with a digital Octagon apparatus for 10 minutes at amplitude 7.The results are reported in FIG. 8. The fine fraction of themicrocapsules above 250 micron is not less than 80%.

TABLE 3 Assay Values for Fexofenadine in Microcapsule Batches withVaried Coating Levels Assay (mg/g) Sample Found Theoretical SAMPLE 8832.7 852.9 (13% average coating weight) SAMPLE 9-D 802.1 813.7 (17%average coating weight) SAMPLE 6-D2 767.3 784.3 (20% average coatingweight)

As shown in Table 3 the assay values of the microcapsules, are close tothe theoretical values (98-99%).

The amount of residual solvent (cyclohexane) is always below 100 ppm forall microcapsules that are prepared in laboratory scale.

1.2 Industrial Scale Microencapsulation

Fexofenadine microcapsules at different levels of ethylcellulose (15, 18and 20%) are prepared by the coacervation process in an 80 gallonstainless reactor, and using a fluid bed apparatus for the drying step.Fexofenadine HCl (code 1) and Fexofenadine HCl (code 2)) are used forthe preparation of microcapsules. Microcapsules with a 15%ethylcellulose are prepared (Sample 71); the “in vitro” dissolution ofSAMPLE 72 and SAMPLE 73 (both are prepared with a different startingfexofenadine (code 2). No significant differences are discerned betweenthe microcapsules that are prepared with different API batches(Mann-Whitney non parametric statistical analysis, p=0.05).

Microcapsules with ethylcellulose levels of 15, 18, and 20% areproduced. The microencapsulation trials are carried out by placing theAPI and the inactive ingredient(s) into the 80 gallon reactor, thenadding fresh cyclohexane. The temperature parameters and stirringconditions of the cycle are set as previously described. At the end ofthe thermal cycle; the paddle rotation is stopped and the product isallowed to settle. The supernatant is removed using a vacuum pump, andfresh solvent is added. The mixture is stirred for short time.Subsequently, the microcapsules are allowed to precipitate again andpart of the cyclohexane is removed for a second time. The microcapsulesare then filtered in a fluid bed equipped with a 70 μm stainless steelsieve on the bottom under inert nitrogen atmosphere and under-vacuum.After the solvent removal, the microcapsule slurry is dried in the samefluid bed to a residual cyclohexane level below 3000 ppm. The productthat is obtained is manually discharged from the fluid bed chamber andsieved through a 840 μm stainless steel sieve.

TABLE 4 Microcapsules batch compositions. SAMPLE 74 SAMPLE 75 SAMPLE 76SAMPLE 77 Material (Kg) 15% EC 15% EC 15% EC 15% EC Fexofenadine 28.3328.33 28.33 28.33 Ethylcellulose 5.00 5.00 5.00 5.00 Wash No No Yes YesAssay - 836.7 825.9 832.3 850.7 experimental (mg/g)

The dissolution profiles of fexofenadine microcapsules in buffer pH 6.82nd fluid JP (ethylcellulose level 15%) are displayed in FIG. 9.

1.3 Dissolution Test of Microcapsules

The microcapsule prototypes have improved wettability when a smallamount of a surfactant such as DOSS is added to the dissolution media.

Dissolution tests on microcapsules are performed by adding a smallamount of surfactants to the dissolution media.

FIG. 10 shows the dissolution profile of microcapsules having a 15% EC(SAMPLE 4) with or without 0.5 mL of DOSS 0.01M in the dissolutionmedia.

Comparison with dissolution rates of commercial Allegro® tabletformulations is carried out using a USP paddle is reported in Table 5.

TABLE 5 Dissolution of Fexofenadine Microcapsule and Allegra ® Tablets %drug released (SD) Sample EC 5 min. 15 min. 30 min. 45 min. SAMPLE 7 20%17 (1) 46 (4) 77 (6) 88 (2) SAMPLE 4 15% 30 (1) 78 (2) 97 (1) 95 (2)SAMPLE 1 10% 92 (1) 97 (1) 96 (1) 96 (1) *Allegra ® tablets 79 (3) 96(3) 98 (3) 98 (3) *Without addition of 0.5 mL of 0.01M DOSS solution.

This comparison indicates that at 15% and 10% ethylcellulose levels, thedissolution of microencapsulated fexofenadine is similar to that of thetablet formulations. Taste evaluation indicates that a 15% coatingprovides acceptable taste characteristics.

Dissolution values using an official analytical dissolution method usinga pH 6.8 buffer (2°nd Fluid for dissolution test, JP 15) and assays ofthe different batches of microcapsules are summarized in tables 6-8.

TABLE 6 Microcapsules with 15% EC Assay and Dissolution Rate Assay(mg/g) buffer pH 6.8 JP 2° fluid + Theo- 0.5 mL DOSS 0.01M reticalAnalytical % drug released (SD) Sample value value 5 min 15 min 30 min45 min SAMPLE 4 850 848.0 30 (1) 78 (2) 97 (1) 95 (2) SAMPLE 850 840.631 (2) 74 (6) 94 (2) 96 (1) 10 SAMPLE 850 843.7 38 (2) 85 (9) 98 (2) 98(2) 11

Microcapsules with a 15% ethylcellulose are prepared (SAMPLE 71) andwetted (by the in-situ process at lab scale, SAMPLE 71/A) anddissolution compared in Table

TABLE 7 Microcapsules with 17% EC Assay and Dissolution Rate Assay(mg/g) buffer pH 6.8 JP 2° fluid + Theo- 0.5 mL DOSS 0.01M reticalAnalytical % drug released (SD) Batch value value 5 min 15 min 30 min 45min SAMPLE 830 824.7 22 (2) 56 (3) 83 (2) 92 (1) 12 SAMPLE 830 826.7 23(2) 58 (7) 82 (3) 91 (1) 13 SAMPLE 9 830 815.3 23 (1) 55 (1) 85 (4) 93(1)1.4 Wetted Microcapsules Preparation

The hydrophobic nature of ethylcellulose gives rise to some drawbackswhen the microcapsules are used in aqueous environment. When thefinished dosage form containing such microcapsules is placed into aglass of water, the hydrophobic microcapsules tend to float and formaggregates (e.g. clumps or cluster) and some tend to attach to the glasswall.

The improved wettability of the microcapsules is achieved by treatingthe microcapsules with a minimal amount of a surfactant (WettingTreatment). Several different wetting ingredients are investigated(e.g., sodium lauryl sulfate; sodium docusate; sucrose fatty acid ester;hydroxypropylcellulose and polyethylene glycol 600, 1000, 3350 and 6000,Lutrol F68; etc.).

Wetted treatment of the microcapsules that is performed with surfactantsis carried out either by suspending the microcapsules in a surfactantsolution, or by spraying the microcapsules with a surfactant solutionusing for example a fluid bed coating as described below or othersuitable equipment.

Wetting Process by Suspension.

The process is carried out by suspending the microcapsules (e.g., SAMPLE3, 15% average coating weight) in docusate sodium (DOSS) dilutedsolutions in cyclohexane. The suspension is mixed for about 15 min at200 rpm, and Syloid 244 is then added to the mixture with stirring. Themicrocapsules are recovered by filtration using standard equipment. Themicrocapsules are then dried at room temperature for about 16 hours andsieved using a 300 micron sieve. The DOSS solution that is added to themicrocapsules preferably contains more than 0.25% of DOSS. The followinglots are prepared: SAMPLE 8 (13% average coating weight), SAMPLE 19-D(15% average coating weight) SAMPLE 9-D (17% average coating weight) andSAMPLE 6-D (20% average coating weight).

Wetting Process by Fluid Bed.

The process is performed using a fluid bed coater that is equipped witha Wurster Insert, and coating microcapsules with a surfactant solutionaccording to standard spraying procedures. The treated microcapsules arethen sieved through a 300 micron sieve. SAMPLE 20-D, having 15% averageEC weight, is prepared. Wetted microcapsules that are obtained arereadily suspendable in aqueous environment without giving rise tosignificant aggregation and water repellence. Reproducibility of thewetting treatment is checked by dissolution testing. “in vitro”dissolution values, assay and impurity of the batches of microcapsulesare checked as is reported in the following part.

Laboratory-Scaled Wetting Treatment

The wetting process is carried out in a top-spray fluid bed apparatus byapplying an aqueous solution of sodium docusate and dispersed silicondioxide. Three different levels of surfactants: 0.45, 0.60 and 0.75%,are applied onto 400 g of microcapsules SAMPLE 78 (15% EC). The resultsthat are obtained are listed in Table 8.

TABLE 8 “In vitro” dissolution values and drug assay for differentbatches. Na Docusate Silicon Dioxide Fexofenadine DRT buffer pH 6.8 2ndfluid JP Batch (%) (%) (mg/g) 5 min 10 min 15 min 30 min 45 min SAMPLE0.75% 2.25% 824.5 82 ± 2 95 ± 2 94 ± 1 95 ± 1 94 ± 1 14 SAMPLE 0.60%2.27% 825.7 84 ± 1 94 ± 2 94 ± 1 94 ± 1 93 ± 1 15 SAMPLE 0.45% 2.27%826.8 76 ± 2 91 ± 1 93 ± 1 93 ± 1 93 ± 1 16

Industrial-Scaled Wetting Treatment.

The wetting treatment is carried out at an industrial scale directlyonto an 18 inch fluid bed apparatus, and a series of wettedmicrocapsules batches SAMPLE 17 and SAMPLE 18 are produced. The wettingdispersion is loaded into the fluid bed using a Watson-Marlow pumpequipped with a Marprene® tube. The theoretical composition is reportedin Table 9 and the dissolution profiles are showed in Table 10 and FIG.11 respectively. Additionally, the water content (Karl Fisher analysis)of SAMPLE 18 is measured (0.38%).

TABLE 9 Theoretical composition of industrial wetted microcapsules.Fexofen- Docu- Silicon Drug DOSS adine sate Dioxide Assay Assay batchmic (%) (%) (%) (mg/g) (mg/g) SAMPLE 17 SAMPLE 78 0.60 2.27 805.2 ± 3.35.9 ± 0.1 (coating 15%) 97.13 SAMPLE 18 SAMPLE 78 0.60 2.27 819.7 ± 1.85.7 ± 0.2 (coating 15%) 97.13

TABLE 10 “In vitro” dissolution values of industrial wettedmicrocapsules. Values in buffer pH 6.8 2^(nd) fluid JP batch 5 min 10min 15 min 30 min 45 min 60 min SAMPLE 66 ± 3 90 ± 2 94 ± 1 95 ± 1 94 ±1 94 ± 1 17 SAMPLE 69 ± 1 90 ± 2 93 ± 1 94 ± 0 94 ± 0 94 ± 1 181.5 Analysis and Dissolution Test of Wetted Microcapsules

Assay and impurities are analyzed for different samples

TABLE 11 Total Impurities of Wetted Microcapsules Prepared withDifferent Amounts of EC Impurity (%) MDL Sample 102,038 Unknown. TotalSAMPLE 8 (13% coat) 0.03 0.05 0.08 SAMPLE 9-D (17% coat) 0.03 0.04 0.07SAMPLE 6-D2 (20% coat) 0.04 0.05 0.09

As shown in Table 11 the assay values of the wetted microcapsules areclose to the theoretical values (98-99%) and the total level ofimpurities is lower than 0.1% for all samples tested.

The dissolution of wetted microcapsules is carried out using pH 6.8 JP2°nd fluid. These results are summarized in Table 12 below and some ofthem are also presented as a graph in FIG. 12.

TABLE 12 Percent Fexofenadine Release from wetted Microcapsules atVarious Time Points for Four Different Ethylcellulose Levels Drugrelease. % (SD) n = 3 Sample 0 min 5 min 15 min 30 min 45 min SAMPLE 8(13% coat) 0 59 (4) 97 (4) 98 (1) 97 (1) SAMPLE 19-D (15% coat) 0 44 (2)90 (3) 97 (1) 96 (1) SAMPLE 9-D (17% coat) 0 34 (3) 83 (5) 97 (2) 97 (1)SAMPLE 6-D2 (20% coat) 0 24 (1) 62 (3) 89 (1) 97 (1) -SAMPLE 20-D (15%coat) 0 81 (4) 95 (2) 95 (2) 95 (2)

Samples with average coating weight levels of 13%, 15% and 17% release80% of the fexofenadine within 15 minutes. The dissolution rate isconsistent with the EC level; that is, samples with higher coatinglevels exhibit a slower dissolution rate, while samples with lowercoating levels exhibit a more rapid rate of release. Notably, the batchis treated with a surfactant applied with fluid bed (SAMPLE 20-D) has afaster release rate (80% release within 5 minutes) (see also FIG. 13)

Assay of the batches of wetted microcapsules and their “in vitro”dissolution values are summarized in Tables 13-20.

TABLE 13 Assay of Microcapsules with 13% EC with Wetting Treatment Assay(mg/g) Theoretical Analytical Sample value value SAMPLE 21-D 852.9 826.2SAMPLE 22--D 852.9 826.0 SAMPLE 23-D 852.9 832.7

TABLE 14 Assay of Microcapsules with 15% EC with Wetting Treatment Assay(mg/g) Theoretical Analytical Sample value value SAMPLE 24--D 833.3 N.A.SAMPLE 11-D 833.3 828.9 SAMPLE 25--D1 833.3  N.A: SAMPLE 26-D1 833.3N.A.

TABLE 15 Assay of Microcapsules with 17% EC with Wetting Treatment Assay(mg/g) Theoretical Analytical Sample value value SAMPLE 12D 813.7 799.6SAMPLE 13-D 813.7 805.1 SAMPLE 9-D 813.7 802.1

TABLE 16 Assay of Microcapsules with 20% EC with Wetting Treatment Assay(mg/g) Theoretical Analytical Sample value value SAMPLE 6-D2 784.3 767.3SAMPLE 27-D 784.3 N.A.

TABLE 17 “In vitro” dissolution values of Microcapsules with 13% EC withWetting Treatment buffer pH 6.8 JP 2° fluid. No surfactant added drugreleased (SD) n = 3 Sample 5 min 15 min 30 min 45 min SAMPLE 21-D 60 (3)95 (1) 96 (2) 95 (1) SAMPLE 22D 55 (5) 95 (1) 96 (1) 96 (1)

TABLE 18 “In vitro” dissolution values of Microcapsules with 15% EC withWetting Treatment buffer pH 6.8 JP 2° fluid. No surfactant added drugreleased (SD) n = 3 Sample 5 min 15 min 30 min 45 min SAMPLE 24--D 52(1) 95 (1) 98 (1) 98 (1) SAMPLE 11-D 47 (2) 93 (3) 97 (1) 97 (1) SAMPLE25--D1 51 (4) 92 (2) 96 (1) 95 (1) SAMPLE 26--D1 44 (2) 90 (3) 97 (1) 96(1)

TABLE 19 “In vitro” dissolution values of Microcapsules with 17% EC withWetting Treatment buffer pH 6.8 JP 2° fluid. No surfactant added drugreleased (SD) n = 3 Sample 5 min 15 min 30 min 45 min SAMPLE 12-D 30 (2)77 (7) 98 (2) 99 (1) SAMPLE 13--D 33 (2) 82 (3) 99 (2) 99 (1)

TABLE 20 “In vitro” dissolution values of Microcapsules with 20% EC withWetting Treatment buffer pH 6.8 JP 2° fluid. No surfactant added drugreleased (SD) n = 3 Sample 5 min 15 min 30 min 45 min SAMPLE 27-D 20 (1)56 (2) 85 (1) 96 (1)

“In vitro” dissolution values are in agreement with amount ofethylcellulose that is applied. Batch to batch variability, among thesamples with the same coating level, is significantly reduced due to theimproved wettability and dispersion capability of the microcapsules. Bycomparing dissolution profile of these wetted microcapsules with thecorresponding unwetted microcapsules it is shown that these wettedmicrocapsules in surfactant-free medium exhibit a higher dissolutionprofile (Tables 21-24).

TABLE 21 “In vitro” dissolution values of Microcapsules with 13%Ethylcellulose with or without Wetting Treatment 0.5 ml DOSS buffer pH6.8 JP 2º fluid Mic 0.01M % drug released (SD) Sample Wetted Added 5 min15 min 30 min 45 min SAMPLE 21 no Yes 50 (1) 94 (2) 97 (1) 96 (1) SAMPLE21-D yes No 60 (3) 95 (1) 96 (2) 95 (1)

TABLE 22 “In vitro” dissolution values of Microcapsules with 15%Ethylcellulose with or without Wetting Treatment 0.5 ml DOSS buffer pH6.8 JP 2º fluid Mic 0.01M % drug released (SD) Sample Wetted Added 5 min15 min 30 min 45 min SAMPLE 11 no Yes 38 (2) 85 (9) 98 (2) 98 (2) SAMPLE28-D yes No 47 (2) 93 (3) 97 (1) 97 (1)

TABLE 23 “In vitro” dissolution values of Microcapsules with 17%Ethylcellulose with or without Wetting Treatment 0.5 ml DOSS buffer pH6.8 JP 2º fluid Mic 0.01M % drug released (SD) Sample Wetted Added 5 min15 min 30 min 45 min SAMPLE 12 No Yes 22 (2) 56 (3) 83 (2) 92 (1) SAMPLE12-D Yes No 30 (2) 77 (7) 98 (2) 99 (1)

TABLE 24 “In vitro” dissolution values of Microcapsules with 20%Ethylcellulose with or without Wetting Treatment 0.5 ml DOSS buffer pH6.8 JP 2º fluid Mic 0.01M % drug released (SD) Sample Wetted Added 5 min15 min 30 min 45 min SAMPLE 27 No Yes 15 (1) 39 (3) 63 (4) 83 (6) SAMPLE27-D Yes No 20 (1) 56 (2) 85 (1) 96 (1)

Wetted microcapsules demonstrate acceptable wettability anddispersibility in all media that are tested, without the need of addingsurfactant to the dissolution media buffer. FIG. 14 compares thedissolution profiles of microcapsules of fexofenadine in different mediawith and without wetting treatment.

From the above data it can be evinced that: small taste maskedmicrocapsules (about 200 μm) are easily dispersible in water; moreover,a suitable release profile is achieved.

1.6 Residual Solvent Microcapsules Batch Analysis

The residual cyclohexane on wetted and unwetted microcapsules that areprepared with different coating levels is measured at less than 100 ppm,based on the weight of the microcapsules. Data are summarized in Table25:

TABLE 25 Residual Solvent of Wetted and Unwetted Microcapsules Preparedwith Different Amounts of Ethylcellulose Wetting Sample Ethylcellulosetreatment Residual Cyclohexane SAMPLE 12 17% no 21 ppm SAMPLE 12--D 17%yes 15 ppm SAMPLE 11 15% no 26 ppm SAMPLE 11-D 15% yes 17 ppm SAMPLE6-D2 20% yes 13 ppm SAMPLE 29 25% no 27 ppm SAMPLE 29--D 25% Yes 36 ppmFrom the above it is clear that residual cyclohexane is within ICHlimits, as is reported in the Q3C(R3) guideline.2 Preparation of Formulated Fexofenadine Microcapsules

Fexofenadine microcapsules are formulated with a series of externalinactive ingredient(s) and/or excipient(s) to prepare and characterizeprototype granulates that: 1) are compatible with the microcapsules; 2)further reduce the bitter taste of fexofenadine; 3) make themicrocapsules easier to swallow; 4) make the microcapsules easier todisperse in water; and/or 5) obtain microcapsules which are easilydispersed and suspended in water.

2.1 Inactive ingredient(s) Selection

The selection of the inactive ingredient(s) is made and binary blends offexofenadine and the evaluated inactive ingredient(s) are prepared invarious drug-to-inactive ingredient(s) ratios and stored at 50° C., wetand dry conditions in hermetically sealed glass vials. At fixed timesthe chemical stability of the blends is evaluated by HPLC test.Generally the results indicate that the API with the selected inactiveingredient(s) are reasonably stable under standard temperature andhumidity conditions.

Different inactive ingredient(s) are also used to evaluate the abilityof microcapsules to be dispersed/suspended (20 mL of distilled water, 36mg of microcapsules), they are reported in Table 26):

TABLE 26 Visual Evaluation of Suspension/Dispersion of FexofenadineMicrocapsule Combined with Different Inactive ingredient(s) Inactiveingredient(s) Suspension Quality Sucrose Good Xylitol Good Sorbitol FairMannitol Fair Lactose Monohydrate Good MCC and sodium FaircarboxymEthylcellulose (Ceolus ®RC-A591NF) β-Cyclodextrin Good

Two formulation approaches are carried out: Direct blend of fexofenadinemicrocapsules with granulated product (excipients) and fluid bedgranulation of fexofenadine with part of the sucrose to be furtherblended with additional granulated sucrose up to final dilution.

2.2 Granulates Preparation and Analysis

Three types of granulates are produced by top-spray fluid bed: 1) asucrose granulate (SG); 2) a sucrose-xanthan gum granulate (SXG); and 3)a sucrose-n cyclodextrin granulate (SβCD). The fluid bed granulationtechnique is selected to produce soft granules with a uniform particlesize and with the ability to dissolve rapidly in water.

SG is obtained by granulating the sucrose with an aqueous solution ofsucrose (5% w/w). The resulting product is dried and the granulefraction between 250-600 μm is selected. The particle size and bulkdensity (0.5 g/mL) of the resulting granules are characterized (FIG.15).

SXG is prepared by granulating the sucrose first with an aqueoussolution of sucrose (5% w/w) and then with aqueous-alcoholic suspensionof xanthan gum. The resulting product is dried and the granule fractionbetween 250-600 μm is selected, the particle size, bulk density (0.5g/mL) and residual ethanol content (<100 ppm) of the resulting granulateare characterized (FIG. 16)

SβCD is produced by granulating a powder mixture of sucrose andβ-cyclodextrin (2:1 w/w) with an aqueous solution of sucrose (5% w/w).The resulting product is dried and the granule fraction between 250-600μm is selected. the particle size and bulk density (0.4 g/mL) of theresulting product are evaluated (FIG. 17).

The compositions of these three granulates are described in Table 27.

TABLE 27 Theoretical Composition of Granulates SG SGX SβCD Sucrose100.0% 98.5% 66.8% Xanthan Gum — 1.5% — β cyclodextrin — — 33.2%2.3 Preparation of Fexofenadine Microcapsule/Granulates Mixtures2.3.1 First Set of Examples of Fexofenadine Microcapsule Blended withSGX, SG and SBCD Granulates)

The samples are prepared using fexofenadine HCl microcapsules at threedifferent average EC weight levels (13%, 17% and 20%). All samplescontain a co-granule of xanthan gum and sucrose (400 mg). In addition tothese materials, each sample contains a quantity of sucrose granules(150 mg) either alone or in combination with an additional inactiveingredient(s), such as, for example, β-cyclodextrin (Beta CDX). The onlyexception to this is SAMPLE 39, which did not contain any additionalsucrose granules.

Additional excipients are added in SAMPLE 30, SAMPLE 31, SAMPLE 32,SAMPLE 33 and SAMPLE 34. Flavorings are added to SAMPLE 30 and SAMPLE31, while β-cyclodextrin (BCD) is added to SAMPLE 32, SAMPLE 33 andSAMPLE 34.

A placebo sample is also prepared (SAMPLE 35). It containsmicroencapsulated talc instead of fexofenadine HCl. Table 28, below,summarizes the qualitative and quantitative compositions of the batches.

TABLE 28 Composition of the Batches Granules Sucrose + Granule XanthamGranules Sucrose + Granule Granules Sachet Microcapsule Gum Sucrose BCDSucrose + Sucrose + mg/ Prototype Batch EC % Mg (SGX) (SG) (SBCD)Yoghurt Strawberry sachet SAMPLE SAMPLE 13 36.0 400 150 586.0 32 23-DSAMPLE SAMPLE 13 36.0 400 150 586.0 36 23-D SAMPLE SAMPLE 17 37.4 400437.4 39 9-D SAMPLE SAMPLE 17 37.4 400 150 587.4 33 9-D SAMPLE SAMPLE 1737.4 400 150 587.4 37 9-D SAMPLE U9A032_E36 Placebo 36.0 400 150 586.035 SAMPLE SAMPLE 13 36.0 400 150 586.0 34 23-D SAMPLE SAMPLE 20 38.5 400150 588.5 38 6-D2 SAMPLE SAMPLE 20 38.5 400 150 588.5 30 6-D2 SAMPLESAMPLE 20 38.5 400 150 588.5 31 6-D2

Homogeneity of dispersion of the resulting granules are characterizedbefore and after agitation/stirring in 20 mL of water.

Additionally, criteria such as sedimentation/settling/floating,re-suspension ability, residual after pouring, and dissolution at pH 6.8JP, 1 mM HCl (pH 3.0) and distilled water of the fexofenadinemicrocapsule/granulate mixture are evaluated as well.

The wettability and dispersion test is performed in 50 mL glass beakerwith 20 mL of de-mineralized water at room temperature (20-25° C.).Specifically, an amount of microcapsules corresponding to 30 mg offexofenadine MCI and the selected inactive ingredient(s) is weighed andpoured into the beaker. The mixture is gently stirred for 10 seconds andthe tendency to form agglomerates, floating, settling, sinking isobserved for 30 seconds. Finally, the suspension is stirred again for 2seconds and poured out, and any residue in the beaker is evaluated.Finally the mouth feel and taste masking characteristics of thefexofenadine microcapsule/granulate mixture is evaluated byadministering the powder into the mouth or on a tablespoon with fewmilliliters of water. The maximum amount of external inactiveingredient(s) and/or excipients that is added to these batches offexofenadine microcapsules (≈36 mg) is 550 mg.

2.3.1.1 Dissolution of Fexofenadine Microcapsules/Granulates Mixtures

A series of tests are carried out using fexofenadine microcapsulescoated with an amount of ethylcellulose ranging from 13% to 20%, andblended with the three different types of granules, as described abovein Table 28. The Wettability/dispersion trials show that the combinationof granulates with the fexofenadine microcapsules did not have anegative impact on their wettability and dispersion in water.Furthermore, good dispersability is shown for the formulations using alimited amount of liquid (tablespoon).

SAMPLE 35 is a placebo prepared with microcapsules of talc instead offexofenadine HCl. SAMPLE 34 has the same composition as SAMPLE 32, andis prepared to confirm the taste masking capability of the microcapsuleswith the lowest coating level. All the prototypes are prepared withgranules of SXG. The SβCD granulate is used in some samples (SAMPLE 32,SAMPLE 33, SAMPLE 34) to evaluate the influence of this inactiveingredient(s) on the reduction of bitterness. SAMPLE 39 is prepared witha reduced level of inactive ingredient(s) to evaluate the effects ofinactive ingredient(s) level on mouth feel. Flavored prototypes SAMPLE30 and SAMPLE 31 are also evaluated. The dissolution profiles of thesamples are reported in the following tables and Figures.

Taste masking tests indicated that all samples generate an immediatesweet sensation, followed by a slight bitterness (after 20-30 sec).However this bitter taste is not recognized as unpleasant.

The results of the dissolution of fexofenadine microcapsules/granulatesmixtures with a 13%, 17%, 20% of polymer is carried out using pH 6.8 JP2°nd fluid are summarized in Table 29-31 and also presented as a graphin FIG. 18, 19, 20. These results are compared to those that areobtained with unformulated microcapsules.

TABLE 29 Percent Fexofenadine Release from Microcapsules and TwoFexofenadine microcapsules/granulates mixtures Using Microcapsules withan Average Ethylcellulose Weight of 13% Drug release % (SD) n = 3 Sample0 min 5 min 15 min 30 min 45 min SAMPLE 8 0 59 (4) 97 (4) 98 (1) 97 (1)(microcapsules) SAMPLE 32 0 66 (2) 96 (1) 97 (1) 96 (1) SAMPLE 36 0 71(2) 100 (1)  99 (1) 98 (1)

The dissolution characteristics of the products are similar to that ofthe microcapsules with a small increase in dissolution rate recordedoverall.

TABLE 30 Percent Fexofenadine Release from Microcapsules and TwoFexofenadine microcapsules/granulates mixtures using Microcapsules withan Average EC Weight of 17% Drug release % (SD) n = 3 Sample 0 min 5 min15 min 30 min 45 min SAMPLE 9-D 0 34 (3) 83 (5) 97 (2) 97 (1)(microcapsule) SAMPLE 33 0 37 (1) 84 (3) 96 (2) 95 (1) SAMPLE 37 0 44(3) 90 (5) 97 (0) 96 (1) SAMPLE 39 0 49 (2) 93 (4) 97 (1) 96 (1)

The dissolution characteristics of the formulated products are similarto that of the microcapsules with a small increase in dissolution raterecorded overall.

The dissolution of formulated product containing microcapsules with anaverage EC weight of 20% is carried out using pH 6.8 JP 2°nd fluid.These results are compared to unformulated microcapsules. These results,are summarized in Table 31 below and also are presented as a graph inFIG. 20.

TABLE 31 Percent Fexofenadine Release from Microcapsules and twoFexofenadine microcapsules/granulates mixtures using Microcapsules withan Average EC Weight of 20% Drug release % (SD) n = 3 Sample 0 min 5 min15 min 30 min 45 min SAMPLE 6-D2 0 24 (1) 62 (3) 89 (1) 97 (0)(microcapsule) SAMPLE 38 0 25 (1) 60 (4) 87 (5) 92 (1)

For each coating level, the dissolution rate of the formulatedmicrocapsule prototypes is similar to the dissolution rate ofmicrocapsules alone (see FIGS. 21-23). The selected inactiveingredient(s) did not seem to affect the dissolution profile of themicrocapsules.

The dissolution rate for formulated product batches is also carried outusing microcapsules with 13% and 17% coatings and tested with 1 mM HCl;and DI water. The results are reported in the hereunder Tables whichalso include the values for dissolution in pH 6.8 JP 2°nd fluid asreported above, and are represented graphically in FIGS. 24-27.

TABLE 32 Dissolution Rate of 13% Average Ethylcellulose WeightMicrocapsules (SAMPLE 8) in Various Dissolution Media Drug release %(SD) n = 3 Dissolution Medium 0 min 5 min 15 min 30 min 45 min 6.8 JP 2°nd 0 59 (4) 97 (4) 98 (1) 97 (1) 1 mM HCl (pH 3.0) 0 63 (1) 98 (1) 98(0) 98 (1) DI water 0 54 (4) 95 (1) 97 (1) 97 (1)

TABLE 33 Dissolution Rate of Fexofenadine microcapsules/granulatesmixtures Containing 13% Average Ethylcellulose Weight Microcapsules(SAMPLE 32) in Various Dissolution Media Drug release % (SD) n = 3Dissolution Medium 0 min 5 min 15 min 30 min 45 min 6.8 JP 2° nd fluid 066 (2) 96 (1) 97 (1) 96 (1) 1 mM HCl (pH 3.0) 0 77 (3) 98 (1) 97 (1) 97(1) DI water 0 57 (1) 90 (3) 92 (3) 92 (3)

TABLE 34 Dissolution Rates of 17% Average Ethylcellulose WeightMicrocapsules (SAMPLE 9-D) in Various Dissolution Media Drug release %(SD) n = 3 Dissolution Medium 0 min 5 min 15 min 30 min 45 min 6.8 JP 2°nd fluid 0 34 (3) 83 (5) 97 (2) 97 (1) 1 mM HCl (pH 3.0) 0 36 (2) 93 (2)97 (1) 97 (1) DI water 0 35 (3) 74 (3) 88 (1) 96 (1)

Dissolution rates of sachet prototype SAMPLE 33, containing microcapsuleSAMPLE 9-D (17% average ethylcellulose weight) are reported below inTable 35.

TABLE 35 Dissolution Rates of Fexofenadine microcapsules/granulatesmixtures Containing 17% Average Ethylcellulose Weight Microcapsules(SAMPLE 33) in Various Dissolution Media Drug release % (SD) n = 3Dissolution Medium 0 min 5 min 15 min 30 min 45 min 6.8 JP 2° nd fluid 037 (1) 84 (3) 96 (2) 95 (1) 1 mM HCl (pH 3.0) 0 52 (4) 93 (3) 96 (3) 96(2) DI water 0 41 (1) 80 (1) 89 (1) 90 (0)

The dissolution rates of the formulated prototypes are similar to thedissolution profile of the corresponding microcapsules. The inactiveingredient(s) that is used do not appear to affect the dissolutionprofile of the microcapsules.

2.3.2 Second Set of Examples of Formulated Fexofenadine MicrocapsulesBlended with SC and SGX Granulates)

A second series of fexofenadine products is prepared (Table 36). Thesecompositions are prepared based on the following criteria: 1) prototypesare formulated using microcapsules with 13% or 15% coating; 2)β-cyclodextrin is not used; 3) a unique amount of flavour, banana orstrawberry, is used for all the prototypes; 4) the flavour is introducedin the formulation mixed with the SG granulate and with a small amountof silicon dioxide.

TABLE 36 Composition of Fexofenadine Prototypes-Second Set SAMPLE SAMPLESAMPLE SAMPLE 40 41 42 43 Fexofenadine 36.0 36.0 microcapsule 13%Fexofenadine 37.0 37.0 microcapsule 15% SG granulate + 150.0 150.0banana flavour + silicon dioxide SG granulate + 150.0 150.0 strawberryflavour + silicon dioxide SGX granulate 400.0 400.0 400.0 400.0 Total(mg) 586.0 587.0 586.0 587.0

Fexofenadine is released with a fast mechanism (i.e., ≥80% release at 15min.) (Table 37).

TABLE 37 “In vitro” dissolution values of Fexofenadine at pH 6.8 2°Fluid JP, from Prototypes Second Set. Drug release % (SD) n = 3 0 min 5min 15 min 30 min 45 min SAMPLE 40 (13%) 0 65 (2) 95 (4) 96 (3) 96 (3)SAMPLE 41 (15%) 0 60 (2) 97 (3) 97 (3) 97 3)2.3.3 Third Set of Examples of Formulated Fexofenadine MicrocapsulesBlended with SGX Granulates

Additional prototypes are prepared as follows. Fexofenadinemicrocapsules are combined with SGX granules, and the amount of xanthangum is reduced from 1.5 to 1.1% w/w in the SGX granulate so that theconcentration of the xanthan gum remains equal to 1.0% w/w.

TABLE 38 Composition of Third Set Fexofenadine Prototypes Test Drug T1Test Drug T2 Mg % mg % Fexofenadine Microcapsules 36.00 6.15 37.0 6.30Granulate Sucrose/Xanthan 549.10 93.70 549.10 93.55 Gum (1.1% w/w)Silicon Dioxide 0.60 0.10 0.60 0.10 Strawberry flavour 0.30 0.05 0.300.05 Total 586.00 100.00 587.00 100.002.4 Preparation of Examples of Fexofenadine Granules2.4.1 First Set Granulation Fexofenadine Microcaps with Sucrose andXanthan Gum

One part of fexofenadine microcapsules (15% by weight of Ethylcellulose)is granulated together with 6 parts of sucrose powder into a fluid bedfitted with a top spray (Glatt GPCG3). The binding solution that isconsisted of an aqueous solution of sucrose (15% w/w) and xanthan gum(0.5% w/w) is sprayed at room temperature. At the end of the granulationprocess the granules are dried, then the dried granules are removed fromthe fluid bed and sieved. The granules are characterized for particle,size distribution (vibrating sieve test), release profile offexofenadine (dissolution test in USP apparatus IT, using 900 mL of pH6.8 buffer, Japan 2^(nd), at 37° C. and paddle speed of 50 rpm), activeingredient content uniformity and appearance (optical microscopy test).

Content uniformity tests show that fexofenadine microcapsules arehomogeneously distributed into granules: measured average content (n=15)and relevant % RSD are respectively 111 mg/g (theoretical adjustedaccording microcapsules assay: 114 mg/g) and 3.2%. Optical microscopyappears to show that the granulation process results in the embedding ofmicrocapsules in sucrose granules or the adhesion of microcapsules ontosucrose granules.

TABLE 39 Size distribution of granules as obtained and of correspondingmicrocapsules Granules Starting microcapsules Sieve opening Amountretained Amount retained μm % w/w % w/w 600 0.0 NA (0.0) 500 2.7 NA(0.2) 355 21.5 0.0 (1.1) (0.0) 250 38.9 0.1 (1.0) (0.1) 212 16.3 0.2(0.3) (0.0) 180 8.7 0.3 (0.8) (0.1) 125 7.8 1.1 (0.6) (0.3) 90 2.5 26.1(0.2) (1.5) Bottom 1.7 72.3 (0.3) (1.7)

TABLE 40 Amount of fexofenadine released from granules and from thecorresponding microcapsules in pH 6.8 buffer (Japan 2^(nd) fluid).Granules release Microcapsules release SAMPLE 44 Time % of theoretical %of theoretical (min) (n = 6) (n = 6) 5 69 64 (3) (1) 15 97 93 (1) (4) 3099 94 (1) (2) 45 98 93 (1) (3)2.4.2 Second Set of Examples of Granulation Fexofenadine Microcaps withSucrose and Xanthan Gum

One part of fexofenadine microcapsules (15% by weight of ethylcellulose)is granulated together with 14 parts of sucrose powder into fluid bedfitted with top spray (Glatt GPCG3). The binding solution that isconsisted of an aqueous solution of sucrose (15% w/w) and xanthan gum(0.5% w/w) is sprayed at room temperature. At the end of the granulationprocess the granules are dried then the dried granules are removed fromthe fluid bed and sieved.

The granules that are collected are characterized for particle sizedistribution (vibrating sieve test), the release profile of fexofenadine(dissolution test in USP apparatus II, using 900 mL of pH 6.8 buffer,Japan 2^(nd), at 37° C. and paddle speed of 50 rpm), active ingredientcontent uniformity and appearance (optical microscopy test).

Content uniformity tests appear to show that the granules arehomogeneously distributed: average content and % RSD respectively 53.5mg/g. (theoretical value adjusted according microcapsules assay: 54.5mg/g) and 2.8%.

Granules appearance (optical microscopy) is close to that of granulesprepared in the first set using the same batch of microcapsules.

Granulation success is confirmed also by size distribution data(vibrating sieve test): aggregation of sucrose and microcapsules lead tosignificant particle size increase (Table 41). Moreover granules sizedistribution is comparable with that of the granules produced in thefirst set (microcapsules/sucrose weight ratio 1:6)

TABLE 41 Size distribution of granules as obtained in first set and ofcorresponding microcapsules Granules Starting microcapsules Sieveopening Amount retained Amount retained μm % w/w % w/w 600 0.0 NA (0.0)500 1.2 NA (0.2) 355 13.7 0.0 (0.8) (0.0) 250 41.1 0.1 (1.0) (0.1) 21220.3 0.2 (0.1) (0.0) 180 10.9 0.3 (0.8) (0.1) 125 9.2 1.1 (0.5) (0.3) 902.1 26.1 (0.2) (1.5) bottom 1.5 72.3 (0.3) (1.7)

TABLE 42 Amount of fexofenadine released from granules and fromcorresponding microcapsules in pH 6.8 buffer (Japan 2^(nd) fluid).Microcapsules release Granules release Time % of theoretical % oftheoretical (min) (n = 6) (n = 6) 5 69 64 (6) (1) 15 97 93 (4) (4) 30 9994 (4) (2) 45 99 93 (4) (3)2.4.3 Third Set of Examples of Granulation Fexofenadine Microcaps withSucrose and Xanthan Gum

A homogenous final mixture is obtained by granulating fexofenadinemicrocapsules with a portion of the excipients, then subsequentlyblended with the remaining inactive ingredients in a granulated form.Mixtures with similar particle sizes are mixed in a 1:1 w/w ratio. Thisco-granulation process is carried out in a lab-scale top-spray fluid bed(GPCG 3, 7 inches). Microcapsules are combined in ratio of 1:6 w/w withsucrose and granulated using a binder solution of sucrose aqueoussolution (5% w/w) containing 0.5% w/w of xanthan gum.

One batch of granulates, SAMPLE 45, is made by combining microcapsulesin a ratio of 1:6 w/w with sucrose using a binder solution of sucroseaqueous solution (5% w/w) in absence of xanthan gum. The addition of thexanthan gum and the concurrent increase of the amount of sucrose in thebinder solution improves the process of the co-granulation ofmicrocapsules with sucrose. Table 43 lists the PSD of the resultinggranulates, and drug assay as f(PSD):

TABLE 43 PSD of the co-granulate manufactured at lab scale: >600 μm 500μm 355 μm 250 μm 212 μm 180 μm 125 μm 90 μm <90 μm SAMPLE 0.2 1.3 4.719.5 19.4 15.1 22.9 9.0 7.9 45 SAMPLE 0.3 4.4 24.7 38.9 14.9 7.5 6.3 1.81.1 46 U9A333 0.0 0.6 6.3 24.6 20.4 14.2 20.5 7.7 5.8 SAMPLE 0.0 2.721.5 38.9 16.3 8.7 7.8 2.5 1.7 44 SAMPLE 0.0 1.8 10.1 263 16.2 12.2 18.26.6 8.2 47 SAMPLE 3.9 6.9 26.3 36.8 13.3 6.3 5.3 0.9 0.2 48 SAMPLE 4.17.3 31.0 38.8 11.1 4.0 2.5 0.4 0.5 49 SAMPLE 3.9 5.5 23.9 38.8 15.3 7.14.7 0.7 0.1 50

The theoretical assay value is always about 100 mg/g for all themanufactured granulates. Microscopic observation shows that the finefraction (<125 micron) is richer in microcapsules when compared with thelarger fractions.

“In vitro” dissolution values are given hereunder for some of themanufactured granulates

TABLE 44 The dissolution values and drug assays for lab-scale granulatespH 6.8 2nd fluid JP Batch 5 min 15 min 30 min 45 min CUT (n = 15) SAMPLE46 50 ± 3 89 ± 2 95 ± 1 94 ± 1 113.5 (RSD 2.6) SAMPLE 44 64 ± 1 93 ± 494 ± 2 93 ± 3 111.0 (RSD 3.2) SAMPLE 48 44 ± 2 79 ± 2 93 ± 2 95 ± 2108.7 (RSD 2.4) SAMPLE 49 57 ± 2 96 ± 1 99 ± 1 99 ± 2 112.5 (RSD 0.7)

In order to control the fraction of small particles the granulationprocess parameters and the amount of binder solution may be adjusted.

The graph displayed in FIG. 28 correlates three process parameters: theamount of the binder solution sprayed onto the powder, the inlet airhumidity, and the atomizing air pressure. Granulates with a lowerpercentage of the fine fraction (values are reported on the octagonangles in the Figure) are generated using the lowest atomizing pressure,highest amount of binder solution, and the appropriate inlet airhumidity. The co-granulate that is produced has a fine fraction <3% anda drug content with a RSD (relative standard deviation) of less than3.0%.

2.4.4 Fourth Set of Examples of Granulation Fexofenadine Microcaps withSucrose and Xanthan Gum. Industrial Scale

The wetted microcapsules are co-granulated with the sucrose fine powderusing the same binder solution used during the lab-scale studies. Inparticular, 14.70 kg of wet microcapsules are granulated with 102.90 kgof sucrose fine powder (ratio 1:7), using 29.40 kg of binder solution.The obtained granulate is sieved through a 840 μm stainless steel sieve.The sieved product is placed in a double PE bag in plastic drums.

TABLE 45 Theoretical composition of this fexofenadine co-granulatesSAMPLE 52. components % w/w Fexofenadine 9.93 Ethylcellulose 1.75 SodiumDocusate 0.07 Silicon Dioxide 0.27 Sucrose 87.86 Xanthan Gum 0.12

The obtained co-granulate is characterized in terms of PSD, drug, assayas f(PSD), water content (0.13%) and “in vitro” dissolution values in pH6.8 2^(nd) fluid JP. Data are reported in the following tables.

TABLE 46 PSD of the co-granulate manufactured at industrial scale: >600μm 500 μm 355 μm 250 μm 212 μm 180 μm 125 μm 90 μm <90 μm SAMPLE 21.917.5 32.9 21.7 3.9 1.3 0.9 0.0 0.0 51 SAMPLE 4.6 6.5 19.4 29.5 15.5 9.510.9 2.7 1.4 52

TABLE 47 “In vitro” dissolution values in buffer pH 6.8 2^(nd) fluid JPand assay (n = 3). pH 6.8 2nd fluid JP Assay RSD Sample Core 5 min 15min 30 min 45 min (mg/g) % SAM- SAM- 55 ± 3 88 ± 4 91 ± 4 91 ± 4 98.63.9 PLE PLE 52 18

The amount of the fine particles is low. The RSD is between 1.8% and6.0%,

2.4.5 Preparation of Sucrose and Xanthan Granulates

Sucrose granules with a PSD similar to that which is obtained with theco-granulate are prepared. This scale up process is performed directlyonto, the industrial top-spray fluid bed Glatt FB500, 500 L. The processis carried out in a single step: the xanthan gum is directly granulatedwith the sucrose by spraying the same binder solution used for theco-granulation process, however the ethanol is eliminated.

In particular, 147.0 kg of sucrose fine powder and 3.0 kg of xanthan gumare granulated with 20.0 kg of binder solution. At the end of thegranulation process the product is sieved through a 840 μm stainlesssteel sieve and 149.1 kg of granulate is obtained (process yield 97.4%).

TABLE 48 Binder solution and sucrose/xanthan gum granulate SAMPLE 53theoretical composition. % composition components % w/w Kg SAMPLE 53Binder Sucrose 15.0 3.0 2.0 solution Xanthan Gum 0.5 0.1 0.1 DeionizedWater 84.5 16.9 — Powder Sucrose fine powder 88.0 147.0 96.0  XanthanGum 2.0 3.0 1.9

The PSD and water content (0.48%) of the resulting granulates arecharacterized.

TABLE 49 Particle Size Analysis SAMPLE 53 and SAMPLE 54. Sieve (μm)SAMPLE 53 (%) SAMPLE 54 (%) >600 8.6 5.7 500 9.4 9.9 355 23.5 25.3 25030.2 31.8 212 11.2 11.2 180 7.1 5.9 125 6.7 6.3 90 1.7 1.7 <90 1.3 2.2

The two granulates are prepared applying the same process parameters andresulted in compositions with similar PSD compared to the co-granulate(this is an important requirement in order to confirm that thesubsequent mixing step can be successfully carried out).

2.5 Blending of Fexofenadine Granules and Sucrose Granules

The two previous batches of co-granulates and sucrose granulates aremixed with two batches of sugar-based placebo granules having a verysimilar PSD, at a 1:1 w/w ratio with batch sizes of about 200 kg. Thecombination of SAMPLE 51 and placebo SAMPLE 55 is designated as SAMPLE56 after mixing.

TABLE 50 PSD of mixture Batch number SAMPLE 56 (SAMPLE 51(co-granulates) and SAMPLE 55 (sucrose granulates): >600 μm 500 μm 355μm 250 μm 212 μm 180 μm 125 μm 90 μm <90 μm SAMPLE 21.9 17.5 32.9 21.73.9 1.3 0.9 0.0 0.0 51 SAMPLE 18.7 16.2 30.9 23.1 5.3 2.1 1.9 0.7 1.4 55

TABLE 51 PSD of Mixture Batch number SAMPLE 57 (SAMPLE 52(co-granulates) and SAMPLE 53 (sucrose granulates): >600 μm 500 μm 355μm 250 μm 212 μm 180 μm 125 μm 90 μm <90 μm SAMPLE 4.6 6.5 19.4 29.515.5 9.5 10.9 2.7 1.4 52 SAMPLE 8.6 9.4 23.5 30.2 11.2 7.1 6.7 1.7 1.353

The tables below describe the composition of the batches.

TABLE 51 The theoretical composition of the batches. components SAMPLE56, SAMPLE 57 (%) Fexofenadine 5.00 Ethylcellulose 0.88 Sodium Docusate0.04 Silicon Dioxide 0.22 Sucrose 92.75 Xanthan Gum 1.06 Strawberryflavour 0.05

TABLE 53 The drug assay and RSD %: Drug assay Theoretical batch (mg/g),n = 3 assay (mg/g) RSD % SAMPLE 48.1 50.0 5.6 56 SAMPLE 49.0 50.0 3.9 57

The blend homogeneity (n=10) of mixture SAMPLE 57 is: first assay: 50.5mg/g (RSD 5.1%); second assay: 50.7 mg/g (RSD 5.5%). The performedtrials indicate that the average assay is close to the theoretical value(50 mg/g).

The dissolution performance of fexofenadine bulk mix (SAMPLE 57) inbuffer pH 6.8 2^(nd) fluid JP (compared with the respective co-granulate(SAMPLE 52) (n=6)) and in pH 3.0 are reported below

TABLE 54 The dissolution profiles of fexofenadine bulk mix (SAMPLE 57)and the co-granulate (SAMPLE 52) (n = 6) in buffer pH 6.8 2^(nd) fluidJP Time (min) 5 10 15 30 45 60 SAMPLE 52 55 ± 3 82 ± 5 88 ± 4 91 ± 4 91± 4 92 ± 5 SAMPLE 57 62 ± 2 86 ± 7 90 ± 5 92 ± 4 91 ± 4 91 ± 4

The mixing process shows a slight increase in the dissolution rateduring the first five minutes, this effect could be possibly related toa mechanical stress that is involved during the mix.

TABLE 55 The dissolution profiles of fexofenadine bulk mix (SAMPLE 57)in pH 3.0 Time (min) 5 10 15 30 45 60 % fexofenadine 63 ± 10 84 ± 10 92± 9 95 ± 8 94 ± 8 94 ± 8 released

The dissolution data for SAMPLE 57 confirm the fast release.

2.6 Sachet Filling

Strength 15 mg are produced corresponding to 300 mg of mixture. Thefilling machine produces 2 sachets in line (7.0 mm×5.8 mm). The maximumproductivity is 170 sachets/min (speed 85 rpm). The material that isused for the preparation of the sachets is 3LAMINET/M AL12960 (PET 12μm, Aluminium 9 μm, antistatic PE 60 μm).

A feeding screw is present between the bag and the feeding hopper alongwith a sensor to detect the quantity of powder in order to keep theamount of mixture in the hopper consistent (when the volume of themixture is decreased, the screw feeds the hopper). The hopper isbipartite having a left and right filling system, each side is equippedwith a single dosing screw. Inside there are two stirring systems (leftand right) that maintain the mix under gentle agitation during theprocess.

Sachet filling trials are carried out starting from a mixture that isprepared with a co-granulate with different levels of fine particles andPSD In some cases the theoretical assay value of the mixture is lowerand therefore the target strength of each drug content can be variable.

Sachet SAMPLE 58 is produced by using the bulk mix SAMPLE 57 (50.0 mg/gRSD 5.6%). The PSD of the bulk mix. SAMPLE 57 is given in Table 51.Parameters of the machine are set as given in the Table below

TABLE 56 Filling machine process parameters. Parameters values Machinespeed 85 rpm Flow stopper 1.6 mm Weight control on line in exit 54.5 g ±0.7 g

TABLE 57 Limits of acceptance SAMPLE 58. Tests Limits of acceptanceWeight 285-315 mg Mass content T1 = 3.0% (±9 mg) T2 = 5.0% (±15 mg)

TABLE 58 Assay results SAMPLE 58. Shipping case 2 4 6 weight Assayweight Assay Assay sample (mg) (mg/sachet) (mg) (mg/sachet) weight (mg)(mg/sachet) 1 302.1 15.2 295.3 14.4 298.2 14.4 2 310.8 15.5 297.3 14.4296.2 14.2 3 310.7 15.4 309.9 15.1 300.1 14.0 4 314.8 16.1 307.3 15.1300.0 14.1 5 316.1 15.6 302.2 14.9 304.1 14.6 6 298.5 15.3 322.7 15.6291.6 14.8 7 313.5 16.1 306.4 14.7 290.2 14.0 8 310.3 15.8 294.2 14.4298.8 14.3 9 305.8 15.9 307.2 15.2 297.0 14.3 10 304.9 15.7 307.2 14.6297.4 14.4 average 308.8 15.7 305.0 14.8 297.4 14.3 Sd 5.7 0.3 8.4 0.44.1 0.3 RSD 1.8 1.9 2.8 2.7 1.4 2.1 Recovery % 104.7 98.7 95.3 MassContent Mass Content Mass Content variation uniformity variationuniformity variation uniformity AV 7.8 8.0 6.5 6.5 6.3 7.2

The results indicate that 300 mg sachet having mass variation between6.3 and 7.8 and content uniformity between 6.5 and 8.0 are be obtainedwith the fexofenadine microcapsule co-granulate of the invention.

2.6.2 Sachet Filling with Mixture SAMPLE 57>125 μm

Bulk mixture SAMPLE 57>125 micron is prepared from SAMPLE 57 by removingthe fine fraction (<125 micron); this is performed by sieving. The PSDdata of the mixture is reported in Table 59

TABLE 59 SAMPLE sieve 57 > 125 μm >600 10.0 355 37.0 212 39.2 125 13.1<125 0.5

Sachet filling trials are carried out on the 15 mg dose sachet usingthis bulk mixture. The batch number of sachets SAMPLE 79 is obtained.The following Table summarizes the results:

TABLE 60 Assay results SAMPLE 79. Shipping case 2 4 8 weight Assayweight Assay weight Assay Sample (mg) (mg/sachet) (mg) (mg/sachet) (mg)(mg/sachet) 1 318.6 14.1 316.1 13.5 303.7 13.6 2 319.6 14.2 294.5 13.8307.4 13.9 3 308.4 13.9 310.6 13.7 306.3 13.5 4 319.8 14.2 305.2 13.3305.3 13.9 5 319.0 14.0 302.7 14.2 306.8 14.0 6 313.6 14.0 301.3 13.2306.2 13.4 7 317.3 14.0 312.8 13.5 304.5 13.5 8 319.1 14.3 298.5 13.1314.8 13.9 9 309.9 13.7 310.4 13.7 313.1 13.6 10 325.6 14.5 303.5 12.9302.7 116 Average 317.1 14.1 305.6 13.5 307.1 13.7 Sd 5.1 0.2 6.8 0.43.9 0.2 RSD 1.6 1.4 2.2 3.0 1.3 1.5 Recovery 102.2 97.8 99.3 MassContent Mass Content Mass Content variation uniformity variationuniformity variation uniformity AV 4.6 4.5 5.9 7.4 3.0 3.7

Good results in term of filling weight are obtained and moreover theassay of the sachet is practically equal to the theoretical value (13.8mg/g); no segregation phenomena occurs.

2.6.3 Sachet Filling with Mixture SAMPLE 56

Trials are carried out on the 15 mg dose sachet using the bulk mixtureSAMPLE 56. The PSD of the bulk mix is reported in Table 61.

TABLE 61 Assay results for sachets with SAMPLE 56 Shipping case 1 2 3 4weight Assay weight Assay weight Assay weight Assay sample (mg)(mg/sachet) (mg) (mg/sachet) (mg) (mg/sachet) (mg) (mg/sachet) 1 315.115.9 315.0 16.0 313.2 16.4 303.8 16.5 2 310.6 16.7 324.8 16.0 314.9 16.7319.2 15.7 3 318.8 16.9 316.0 16.5 316.8 16.5 303.9 16.3 4 315.1 16.6319.2 16.1 309.1 16.7 305.7 16.8 5 313.3 16.5 323.1 17.0 309.6 16.2302.3 16.7 6 313.5 16.2 314.0 14.5 316.0 15.2 300.4 15.4 7 312.8 15.4312.8 15.2 317.7 15.5 339.1 15.8 8 315.7 15.6 314.2 15.3 314.1 15.7298.9 14.9 9 313.1 16.3 317.5 14.7 315.9 14.6 300.8 15.4 10 312.5 15.8316.4 15.0 314.3 14.7 298.7 14.9 average 314.1 16.2 317.3 15.6 314.215.8 307.3 15.8 Sd 2.1 0.5 3.8 0.8 2.7 0.8 12.0 0.7 RSD 0.7 2.9 1.2 4.90.9 4.8 3.9 4.2 Rec. % 107.9 104.2 105.5 105.6

The assay is coherent with the filling weight, always over thetheoretical of 300 mg; there is a total absence of segregationphenomena, the assay remains very consistent during all the productionand mainly its variability.

2.6.4 Sachet Filling with Industrial Scale Equipment

Further trials are performed using industrial scale equipment; the batchsizes involved are in the Lange of hundreds kilos for the final bulkmixture and in the order of hundreds of thousands of dosage units.

The fexofenadine co-granulates are prepared starting from wettedmicrocapsules. Examples of particles size distribution of wettedmicrocapsules are reported in table 62.

TABLE 62 Particle size distributions of wetted microcapsules (Sievemethodology) >355 μm Between 355 and 125 μm <125 μm 1.0 4.0 95.0 1.0 6.093.0 0.0 2.0 98.0 0.0 1.0 99.0 0.0 2.0 98.0 1.0 2.0 97.0

The co-granulates are prepared and mixed with granulated ingredients;the three batches that are obtained have the same composition as thebatches of Table 51. Trials are carried out on these three batches.

The following table shows data related to Particle Size Distribution, ofthe mixtures and the Assay and corresponding Standard Deviation of thesachets produced for the 3 batches:

TABLE 63 Particle Size Distribution of the mixtures SAMPLE Number SAMPLE59 SAMPLE 60 SAMPLE 61 Sieve opening % retained by each sieve >600 μm 8.2 ± 1.0 9.6 ± 0.7 13.2 ± 2.1 >355 μm 49.4 ± 4.9 46.8 ± 4.3  58.0 ±0.5 >212 μm 36.2 ± 2.5 37.1 ± 2.6  25.4 ± 0.4 >125 μm  5.2 ± 1.4 5.7 ±2.3  2.1 ± 0.8 <125 μm 1.0 0.7 0.7 ± 0.4  1.2 ± 0.7

Each batch of mixture is used to prepare two batches of sachets, one foreach forecasted dosage strength: 15 and 30 mg, where the 30 mgcorresponds to 600 mg of filling weight and the 15 mg to: the 300 mg.

In detail, each batch of mixture gives rise to the following batches ofsachets:

-   -   Mixture sample 59⇒Sachets 62 (300 mg) and 63 (600 mg)    -   Mixture sample 60⇒Sachets 64 (300 mg) and 65 (600 mg)    -   Mixture sample 61⇒Sachets 66 (300 mg) and 67 (600 mg)

The following table shows the experimental values of Assay for eachproduced batch of sachets:

TABLE 64 Assay of the sachets Batch Practical Assay, Practical SD on RSDon Number mg/sachet Assay, % practical assay practical assay A62 14.9 990.4 2.7 A63 14.8 99 0.3 2.0 A64 15.2 101 0.3 2.0 A65 30.6 102 0.5 1.6A66 30.3 101 0.7 2.3 A67 30.9 103 0.6 1.9

Furthermore, sachets containing 600 mg of dry syrup is analysed also interms of “in vitro” dissolution rate, the dissolution test is carriedout at pH=3.0 using n=1.2 samples. The following table reports the dataexpressed for % released after 15 minutes, Standard Deviation andRelative Standard Deviation:

TABLE 65 “In vitro” dissolution data 600 mg batches % released SD RSD 6392 3 3.3 65 93 5 5.4 67 85 3 3.5

From the above it can be evinced that additional filling weights (600and 300 mg per unit) and additional dosage strengths (15 mg and 30 mg offexofenadine HCl per unit) of sachets containing the dry syrup aresuccessfully manufactured.

It will be appreciated that, although specific embodiments of theinvention are described herein for purposes of illustration, variousmodifications may be made without departing from the spirit and scope ofthe invention.

What is claimed is:
 1. A water-suspendable pharmaceutical compositioncomprising (a) a co-granulate of at least one inactive ingredient andtaste-masked immediate release microcapsules comprising fexofenadine anda water-insoluble polymer coating; and (b) at least one granulatedinactive ingredient; wherein the co-granulate (a) and the at least onegranulated inactive ingredient (b) have a fine fraction below 125 μm of<5%, and a fraction over 600 μm of <10%.
 2. The pharmaceuticalcomposition of claim 1, wherein the ratio of the co-granulate (a) to theat least one granulated inactive ingredient (b) is 1:1.
 3. Thepharmaceutical composition of claim 1, wherein said fexofenadine iscrystalline fexofenadine.
 4. The pharmaceutical composition of claim 1,wherein said fexofenadine is fexofenadine hydrochloride.
 5. Thepharmaceutical composition of claim 1, wherein said water-insolublepolymer is selected from the group consisting of ethylcellulose,polyvinyl acetate, cellulose acetate, cellulose acetate butyrate,polyvinyl acetate, ammonio-methacrylate copolymers and mixtures thereof.6. The pharmaceutical composition of claim 5, wherein saidwater-insoluble polymer is ethylcellulose.
 7. The pharmaceuticalcomposition of claim 1, wherein the weight of the water-insolublepolymer of said microcapsules is from about 2% to about 40%.
 8. Thepharmaceutical composition of claim 7, wherein the weight of the waterinsoluble-polymer of said microcapsules is from about 10% to about 20%.9. The pharmaceutical composition of claim 8, wherein the weight of thewater-insoluble polymer of said microcapsules is from about 13% to about18%.
 10. The pharmaceutical composition of claim 4, wherein saidcomposition releases at least about 60% of said fexofenadinehydrochloride within 15 minutes in pH 6.8 JP 2° nd fluid.
 11. Thepharmaceutical composition of claim 10, wherein said compositionreleases at least about 80% of said fexofenadine hydrochloride within 15minutes in pH 6.8 JP 2° nd fluid.
 12. The pharmaceutical composition ofclaim 11, wherein said composition releases at least about 95% of saidfexofenadine hydrochloride within 15 minutes in pH 6.8 JP 2° nd fluid.13. The pharmaceutical composition of claim 1, wherein saidmicrocapsules further comprise a surfactant, glidant or an antistickingagent.
 14. The pharmaceutical composition of claim 13, wherein saidsurfactant is sodium docusate.
 15. The pharmaceutical composition ofclaim 1, wherein said at least one granulated inactive ingredient (b) isselected from the group consisting of a granulated sugar alcohol, and agranulated saccharide.
 16. The composition of claim 1, wherein the atleast one granulated inactive ingredient (b) is a mixture of sucrose andxanthan gum.
 17. The pharmaceutical composition of claim 1, wherein saidcomposition is in the form of a tablet, capsule or sachet.
 18. Thepharmaceutical composition of claim 1, wherein the co-granulate (a) andthe at least one granulated inactive ingredient (b) have a fine fractionbelow 125 μm of <5.0%, and a fraction over 600 μm of <5.0%.
 19. Thepharmaceutical composition of claim 1, wherein the co-granulate (a)consists of taste masked immediate release microcapsules, xanthan gum,and sucrose, wherein the weight ratio of the microcapsules to the(xanthan gum+sucrose) is between 1:6 and 1:7.
 20. The pharmaceuticalcomposition of claim 19, wherein said composition is in the form of asachet.